Ohls Robin K, Das Abhik, Tan Sylvia, Lowe Jean R, Schibler Kurt, Beauman Sandra Sundquist, Bell Edward F, Laptook Abbot R, Baserga Mariana, Patel Ravi M, Carlton David P, Flibotte John, Grisby Cathy, Higgins Rosemary D, Shankaran Seetha, Watterberg Kristi, Hibbs Anna Maria, Carlo Waldemar A, Colaizy Tarah T, Van Meurs Krisa P, Kicklighter Stephen D, Moore Ryan, Sollinger Christina, Chalak Lina F, Ghavam Sarvin, Poindexter Brenda B, Tyson Jon E, Cotten C Michael, Baack Michelle L, Fathi Omid, DeMauro Sara B, Laughon Matthew M, Reynolds Ann Marie, Duncan Andrea F, Winter Sarah, Wilson-Costello Deanne E, Peralta-Carcelen Myriam, Vohr Betty R, Harmon Heidi M, Hintz Susan R, Cavanaugh Brenna, Heyne Roy J, Merhar Stephanie, Mosquera Ricardo, Sewell Elizabeth, Malcolm William F, Richards Laurie A, Benninger Kristen L, Trembath Andrea
Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City.
Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland.
JAMA Pediatr. 2025 May 12. doi: 10.1001/jamapediatrics.2025.0807.
Previous studies suggest that administration of erythropoiesis-stimulating agents darbepoetin or erythropoietin to preterm infants results in fewer transfusions, fewer donor exposures, and improved neurodevelopmental outcome.
To determine if, compared with placebo, preterm infants randomized to weekly darbepoetin would have greater red cell mass during hospitalization and better neurocognitive outcome at 22 to 26 months' corrected age.
DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted between September 2017 and November 2019 for infants 23 0/7 to 28 6/7 weeks' gestation in 19 US Neonatal Research Network centers comprising 33 neonatal intensive care units. Follow-up occurred through January 2023. Infants were randomized by 36 hours after birth to weekly placebo or darbepoetin (10 μg/kg) through 35 weeks' postmenstrual age. Iron administration and transfusions were administered by protocol. Study data were analyzed from June to October 2023.
The primary outcome was the mean cognitive composite score on the Bayley Scales of Infant Development, third edition (Bayley-III) at 22 to 26 months' corrected age. The lowest possible score (54) was assigned to infants who died.
A total of 650 infants (322 darbepoetin; 328 placebo; mean [SD] gestational age, 26.2 [1.7] weeks; 328 female [50.5%]) were enrolled. Five hundred eighty-three infants (291 darbepoetin; 292 placebo) had the primary outcome determined (90% of those enrolled). Mean (SD) cognitive scores were similar between groups: 80.7 (19.5) darbepoetin vs 80.1 (18.7) placebo, adjusted mean difference, -0.23 (95% CI, -3.09 to 2.64). Compared with infants receiving placebo, more infants in the darbepoetin group were transfusion free (40% [127 of 319] vs 21% [70 of 327]; adjusted relative risk [RR], 1.3; 95% CI, 1.2-1.5), received fewer transfusions (mean [SD], 2.3 [3.1] vs 3.3 [3.5]), were exposed to fewer donors (mean [SD], 1.6 [2.3] vs 2.2 [2.3]), had higher red cell mass by week 2 of age (adjusted mean difference, 3.2; 95% CI, 1.7-4.7), and higher mean hematocrit by week 2 of age (adjusted mean difference, 2.8; 95% CI, 2.1-3.6), and were less likely to have bronchopulmonary dysplasia greater than grade 1 (35% [91 of 261] vs 46% [128 of 277]; RR, 0.78; 95% CI, 0.64-0.96). The incidence of retinopathy of prematurity stage greater than 2 was similar between groups, 13% (35 of 273) in the darbepoetin group vs 16% (45 of 279) in the placebo group. There were no differences in adverse effects between groups.
Results of this randomized clinical trial reveal that this dose and dosing schedule of darbepoetin did not improve cognitive scores of preterm infants at 22 to 26 months' corrected age. Darbepoetin significantly increased red cell mass resulting in higher hematocrit values, fewer transfusions, and fewer donor exposures.
ClinicalTrials.gov Identifier: NCT03169881.
先前的研究表明，对早产儿使用促红细胞生成剂（如达贝泊汀或促红细胞生成素）可减少输血次数、减少接触供血者，并改善神经发育结局。
确定与安慰剂相比，随机接受每周一次达贝泊汀治疗的早产儿在住院期间是否会有更大的红细胞量，以及在矫正年龄22至26个月时是否会有更好的神经认知结局。
设计、地点和参与者：这项随机临床试验于2017年9月至2019年11月在美国19个新生儿研究网络中心的33个新生儿重症监护病房对孕周为23 0/7至28 6/7周的婴儿进行。随访至2023年1月。婴儿在出生后36小时内随机分为接受每周一次的安慰剂或达贝泊汀（10 μg/kg）治疗，直至月经后年龄35周。按照方案进行铁剂补充和输血。2023年6月至10月对研究数据进行分析。
主要结局是矫正年龄22至26个月时在贝利婴儿发育量表第三版（Bayley-III）上的平均认知综合得分。对死亡婴儿赋予最低可能得分（54分）。
共纳入650例婴儿（322例接受达贝泊汀治疗；32；328例接受安慰剂治疗；平均[标准差]孕周为26.2 [1.7]周；328例为女性[50.5%]）。583例婴儿（291例接受达贝泊汀治疗；292例接受安慰剂治疗）确定了主要结局（占纳入婴儿的90%）。两组间平均（标准差）认知得分相似：接受达贝泊汀治疗组为80.7（19.5），接受安慰剂治疗组为80.1（18.7），调整后平均差值为-0.23（95%置信区间，-3.09至2.64）。与接受安慰剂治疗的婴儿相比，接受达贝泊汀治疗组中更多婴儿未接受输血（40% [319例中的127例] 对21% [327例中的70例]；调整后相对风险[RR]为1.3；95%置信区间，1.2-1.5），接受输血次数更少（平均[标准差]，2.3 [3.1]次对3.3 [3.5]次），接触供血者更少（平均[标准差]，1.6 [2.3]次对2.2 [2.3]次），2周龄时红细胞量更高（调整后平均差值为3.2；95%置信区间，1.7-4.7），2周龄时平均血细胞比容更高（调整后平均差值为2.8；95%置信区间，2.1-3.6），且发生大于1级支气管肺发育不良的可能性更小（35% [261例中的91例] 对46% [277例中的128例]；RR为0.78；95%置信区间，0.64-0.96）。两组间早产儿视网膜病变大于2期的发生率相似，达贝泊汀治疗组为13%（273例中的35例），安慰剂治疗组为16%（279例中的45例）。两组间不良反应无差异。
这项随机临床试验的结果表明，这种剂量和给药方案的达贝泊汀在矫正年龄22至26个月时并未改善早产儿的认知得分。达贝泊汀显著增加了红细胞量，导致血细胞比容值更高、输血次数更少以及接触供血者更少。
ClinicalTrials.gov标识符：NCT03169881。
